The use of Ketamine by the military in the prehospital environment traces back to the Vietnam war. Originally, Ketamine was cleared for civilian use in the United States as “Ketalar” at the beginning of 1970. At that time, it was valued as a possible “monoanesthetic” drug, capable of delivering analgesia, amnesia, loss of consciousness, and immobility in a single agent (1). Pretty amazing indeed.
The problem was that the drug also had the potential for side effects, such as hallucinations and psychotomimetic reactions. These side effects, in combination with the development of other IV anesthetics, contributed to its diminished role outside of the battlefield. Ketamine still conserved a unique feature amongst drugs of the same class though: a sympathomimetic effect that makes it the perfect (and only?) viable choice when it comes to hemodynamically unstable patients. That is right, sympathomimetic as in sympathetic, not only it will not decrease patient’s blood pressure and respiration, but there is a chance that Ketamine will increase blood pressure.
It sounds perfect, doesn’t it? Combine that with the fact that an overdose is nearly impossible; you now understand why medics from all over the world, conventional and special operations alike, are routinely administering Ketamine as a first line drug when it comes to trauma. Though hallucinations and psychotomimetic reactions are still part of the deal, anybody who has used Ketamine on their patients probably has some stories about it. Dealing with a combative trauma patient in the “field” is at the bottom of any medic’s wish list. The problem of combative patients has been overcome through the years by combining low dosage of benzodiazepines to the administration of Ketamine. But benzodiazepines, such as Midazolam might depress respiration in hypovolemic patients, right? And here we are again, right where we started. Don’t get me wrong, Ketamine does the job (actually jobs) like no other drug, but we are still striving for perfection and improvement. What if somebody invented a better Ketamine? One with half the downs and double the ups? Well, somebody did, and it is closer than you would think.
A little bit of history
The research that led to the discovery of Ketamine roots back to 1956 (2). A pharmaceutical company by the name of Parke-Davis started working on a compound called phencyclidine with the goal of creating an anesthetic agent with analgesic properties. Six years and many chemical compounds later, the union of a ketone and an amine resulted in a “compound with cataleptic, analgesic and anesthetic action but without hypnotic properties” (Mion, 2017, p.572). In just one word, Ketamine. Clinical trials quickly cleared the drug for veterinary use in Europe and shortly after it became available for human use in both the United States and most western European countries in 1970.
Skeptical reactions accompanied Ketamine’s appearance on the market, especially in the United Kingdom where its debut was described as a disaster (2). The hallucinations and psychedelic effects were evaluated as too severe to make it an acceptable all-around agent for induction in the clinical setting. The fact that Propofol, a more refined, expensive, and hence profitable for pharmaceutical companies, intravenous anesthetic was being introduced in the same year, did not help the cause. Ironically, Ketamine was then relegated to veterinary and military medicine applications. Nothing changed until 1997 when a drug by the name of S-ketamine was marketed in Germany as Ketanest. But was it a new drug?
Down the “K hole”…
Chemically, Ketamine as we know it is a racemic compound, meaning that it is a combination of two identical molecules that face each other, mirroring themselves. Such molecules, which are similar but not-superposable due to the mirroring part, are known as stereoisomers. We have a left facing isomer called S-ketamine (aka esketamine) and a right facing one called R-ketamine (aka arketamine). In addition to that, the isomers rotate differently on the chemical plane, and that is why S-Ketamine is indicated as S-(+)- Ketamine (the + sign meaning it is dextrorotary so rotates clockwise) and R-Ketamine is indicated as R-(-)-Ketamine (the – sign meaning it is levorotary so rotates counterclockwise). All of this is relevant because the chemical shape dictates the way the molecules interact with the human body generating slightly different effects. Not only they behave differently from each other, but they also both behave differently from the original racemic compound which is a combination of the two, the well-known Ketamine we have been using until now.
Stay focused; this is where it becomes interesting.
Deeper down the “K hole”
Ketamine’s pharmacodynamics (the way the drug acts on the body) are complex, really complex. Think about your good old morphine, for example. Morphine is an opioid, and opioids bind to opioid receptors to take the pain away. Simple as that. Do you want to reverse it? You have Naloxone which kicks Morphine off the receptors taking its place.
Ketamine, on the other hand, binds to multiple receptors in the brain and that is why
it was researched initially as a “monoanesthetic” drug. These receptors include NMDA and non-NMDA glutamate receptors, nicotinic, muscarinic cholinergic, monoaminergic, and even opioid receptors. Yes, that is a lot of receptors, and to simplify it, we can retrace the most analgesic, amnestic, psychotomimetic, and neuroprotective effects of the compound to its action on the NMDA receptors.
Although, now we know that the drug is composed of two distinct molecules that have different effects. That is known as stereoselectivity, meaning that the results are directly linked to the way the molecules are oriented and rotate into the chemical plane. Clinical trials have proven that
S-Ketamine by itself has a four times stronger affinity when it comes to binding to NMDA receptors than its Siamese twin R-Ketamine. When compared to racemic Ketamine, where we have both stereoisomers working together, that affinity is only two times stronger because the opposite sense of rotation of the molecules somehow balances things out.
That is right, half the dosage of S-Ketamine is going to achieve the same results in
reference to analgesia and anesthesia than racemic Ketamine would.
Another interesting difference is that plasma and brain concentration levels of R-Ketamine are three times stronger than S-Ketamine after administering the same dose, suggesting that the use of the latter by itself should reduce the risk for hallucinations and psychotomimetic reactions. Pharmacokinetics (the way the body acts on the drug) are similar for both isomers. S-Ketamine
shows a slightly faster elimination rate though, which means the drug is cleared from the system in a shorter timeframe. The hemodynamic response is sympathomimetic for both molecules. Other than the mere numbers, it is essential to state that most of the subjects of clinical trials have described S-Ketamine as a “cleaner hole” producing less unpleasant effects when compared to usual racemic Ketamine.
So now what?
Now that was interesting, but it is time to understand what S-Ketamine would change for the end user, the good old soldier/operator-medic on the field. First of all, it would make it possible to achieve the same effect, whether it is conscious sedation or procedural analgesia, with half the traditional dosage. It might be overlooked as something with poor relevance, at the end of the day somebody could say: a vial is a vial, and I know my protocols, so why should I change them if the effect is the same? Well here comes the trick. Even if science has demonstrated it to be likely for side effects to be similar with both S-Ketamine and racemic Ketamine, it has also shown that side effects are related to the dosage and the plasma and cerebral concentration of the drug (1). With S-Ketamine you would administer a considerably smaller dosage to reach the same purpose, meaning that side effects would still be possible but way less likely to happen, in the order of 50% less.
Right now, S-Ketamine is already part of many European NATO military protocols. Germany, Austria, Sweden, and Norway have been using the drug for years, reporting successful results with half or less the usual dosage of traditional Ketamine hydrochloride. A 0.25-1mg/Kg/Hr dose of S-Ketamine is currently in the indications of those countries’ militaries for the maintenance of conscious sedation in trauma patients on the battlefield (3). Tactical Combat Casualty Care current indications are to start with 20 mg of a slow intravenous push of racemic Ketamine followed by 10 mg bumps as needed, and the initial dose rises at 50 mg if you choose the intramuscular route (4). There is currently no reference to S-Ketamine in any protocol from the United States military, mainly because the drug has never been introduced on the market nor approved by Food and Drugs Administration in the first place.
But things might change, sooner than later.
It’s all about mental health
Off-label use of Ketamine as an anti-depressant drug is going on in the U.S. for years (5). Intravenous slow infusion of the drug (0.5 mg/kg for 40 minutes) is known as a solution for treatment-resistant depression with an impressive rate of immediate reduction of suicidal thinking (6). Concerns about side effects of Ketamine though, even in this field of application, have not changed. That is why the attention in the U.S. has been lately turning towards
S-Ketamine, especially after the good reports coming from Europe. American trials on
S-Ketamine as a treatment for depression started in 2015. Preliminary results have been acclaimed very positively at the American Psychiatric Association Annual Meeting, that took place in New York last May (7). The drug is now undergoing phase 3 trials from the Food and Drugs Administration, meaning that it could be cleared for the American market as early as January 2019.
It would be initially classified as an anti-depressant drug, that is true, but the right attention from the military would make it easy to clear it for battlefield analgesia once it is already FDA approved.
The science behind S-Ketamine is pretty straightforward. The drug gets the job done
with smaller dosages and fewer side effects, possibly sparing the administration of benzodiazepines to control them.
I have personally administered both drugs to trauma patients, feeling way more comfortable using S-Ketamine; also, because a lower dosage implies less production of secretions, making it way easier to manage airways where suction may be unavailable or difficult to administer. The biggest downside I can see right now is economic. Racemic Ketamine went generic years ago, meaning it can be manufactured without trademark expenses. S-Ketamine, on the other hand, will be marketed for scratch with inevitably higher costs for purchase.
Planning for the wars of the future
Military medicine is moving towards Prolonged Field Care and delayed evacuation scenarios, for both conventional and special operations medics. Iraq and Afghanistan offered limited challenges about pain management on the battlefield because of the average evacuation time. Tactical Combat Casualty Care sufficed and was proven successful, but times are now changing.
We should be planning on the wars of the future and not on those of the past. In the
future Special Operations Combat Medics, Expeditionary Combat Medics, 18Ds, Special Operation Independent Duty Corpsman, and NATO Special Operations Combat Medics alike will have an answer to the question of prolonged field analgesia. 20mg of IV Ketamine with 10mg bumps as needed will not be an adequate solution, which I can tell you. More education will be required…and eventually more sufficient drugs.
Is S-Ketamine the answer? At this point, I cannot say, and military research must eventually prove it. What I know is that if I had the choice, I would pick an agent that is twice as strong with fewer side effects any day. Personal experience is of poor scientific relevance if not backed up by the appropriate research, but I saw myself with two casualties in the same incident receiving the two different drugs for pain control. Guess which patient needed Midazolam to stop screaming and pulling his IV lines?
I suggest you look at your protocols and start thinking about how reducing Ketamine dosages without reducing the desired effect would impact them and the care you deliver. You might be surprised to find that S-Ketamine does have a place in your med bag after all.
References: (1) Ketamine: Teaching an Old Drug New Tricks
Rainer Kohrs, MD, and Marcel E. Durieux, MD
Department of Anesthesiology, University of Virginia Health Center, Charlottesville, Virginia
(2) History of anesthesia: The ketamine story – past, present and future
European Journal of Anaesthesiology (EJA): September 2017 – Volume 34 – Issue 9 – p 571
(3) Advanced Medical First Responder course study material International Special Training Centre, Pfullendorf, Germany 2015
(4) Tactical Combat Casualty Care Guidelines 2017
(5) Ketamine for depression: evidence, challenges and promise
Carlos A Zarate and Mark J Niciu
World Psychiatry. 2015 Oct; 14(3): 348–350.
(6) A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of
Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With
Treatment-resistant Depression (TRANSFORM-2) Published online 2015 Sep 25. doi: 10.1002/wps.20269
(7) Johnson & Johnson Press Release. Esketamine Receives Breakthrough Therapy
Designation from U.S. Food and Drug Administration for Major Depressive Disorder
with Imminent Risk for Suicide.
Available at: https://www.jnj.com/media-center/press-releases/esketamine-recieves-breakthroughtherapy-designation-from-us-food-and-drug-administration-for-major-depressive-disorder-withimminent-risk-of-suicide. Accessed May 2018.
Perioperative nonopioid infusions for postoperative pain management
Honorio T. Benzon MD, in Essentials of Pain Medicine (Third Edition), 2011
Husband, trauma junkie, adrenaline freak.
A NATO Special Operations Combat Medic serving with a high-readiness European airborne unit. Devoted to the delivery of the best patient care in those places where only a few can venture, on a perennial journey towards self-improvement. He graduated the Australian Diploma of Paramedical Science (PLAR) and is now a student at the prestigious University College of Cork. Check his Instagram at @maccheronimedic